The presence of a normal libido, defined as the urge to engage in sexual activity and intercourse, is an important component of an individual's well-being. Low or decreased libido is a common complaint in women. Such complaints are observed in pre peri- as well as post-menopausal women.
A low libido is characterised by a lack of interest in sexual intercourse and/or the lack of ability to achieve orgasm. A decreased libido may be accompanied by a decrease in intensity of orgasm. It is important to note that a decrease in libido is often associated with a profound sense of loss of a once normal and active interest in sexual activity.
U.S. Pat. No. 6,284,263 (Place) is concerned with a method of treating sexual dysfunction in female individuals, comprising bucally administering a therapeutically effective amount of an androgenic agent, a progestin and an estrogen. The US-patent specifically mentions the following estrogens: 17α-estradiol, 17β-estradiol, ethinyl estradiol, pharmaceutically acceptable esters and ethers of 17α-estradiol, 17β-estradiol and ethinyl estradiol, estriol, estriol succinate, polyestrol phosphate, estrone, estrone acetate, estrone sulfate, piperazine estrone sulfate, quinestrol, mestranol and conjugated equine estrogens. As explained in the US-patent, vaginal atrophy and dyspareunia are a common cause of sexual dysfunction.
In an article by Grio et al., Minerva Ginecol, “Sexuality in menopause. Importance of adequate replacement therapy” (1999), 51(3), 59-62, it is observed that estrogen deficiency in menopause is responsible for reduced libido and uncomfortable trophic disorders of the urogenital tract leading to reduced vaginal lubrication and severe alterations affecting sexual function. The authors treated 102 menopausal patients who presented reduced libido and orgasmic difficulties, as well as other menopausal problems, with 17-β estradiol and norethisterone acetate using a transdermal route. It is noted in the article that the main advantage offered by the transdermal route is that estrogens bypass the liver and reach the target organs in an unmodified manner. The authors conclude that the use of 17-β estradiol and norethisterone acetate can effectively modify menopausal symptoms, improving both quality of life and sexual function.
Well-known estrogens, in particular biogenic estrogens (i.e. estrogens that occur naturally in the human body), are eliminated from the blood stream very quickly. For instance, for the main human biogenic estrogen 17β-estradiol the half-life is around 1 hour. As a result, between separate administration events, blood serum levels of such biogenic estrogens tend to fluctuate considerably. Thus, shortly after administration, the serum concentration is usually several times higher than the optimum concentration. In addition, if the next administration event is delayed, serum concentrations will quickly decrease to a level where the estrogen is no longer physiologically active.
The most important synthetically altered estrogenic steroid is 17α-ethinyl estradiol (EE). This estrogen is dominant in oral hormonal contraception. Apart from EE, mestranol has been used in a few cases; mestranol is a “prodrug” that is metabolised to EE in the organism. The liver is a target organ for estrogens. The secretion activity that is affected by estrogens in the human liver includes increased synthesis of transport proteins CBG, SHBG, TBG, several factors that are important for the physiology of blood clotting, and lipoproteins. The strong hepatic estrogenicity of ethinyl estradiol and diethylstilbestrol (DES), especially their effect on haemostasis factors, may explain why these synthetic estrogens have been associated with the enhanced risk of thromboembolism. Other undesirable side-effects that have been reported in relation to the use of synthetic estrogens include, fluid retention, nausea, bloating, chlolelithiasis, headache, breast pain and an enhanced risk of breast cancer with longer term usage.
The aforementioned deficits are of considerable clinical significance when commonly known biogenic or synthetic estrogens are applied. Consequently, there is an as yet unmet need for estrogens that do not display these deficits and which can suitably be employed in a method of increasing libido in women.